Biomimetic cerasome has drawn much attention as a novel drug delivery system because its atomic layer of polyorganosiloxane surface imparts higher morphological stability than conventional liposomes and its liposomal bilayer structure reduces the overall rigidity and density greatly compared to silica nanoparticles. But, the issues about the interactions between cerasomes and biological systems have not been addressed as far as we could find. Herein, we reported cellular uptake of cerasomes and their biological effects toward human umbilical vein endothelial cells (HUVECs) compared with silica nanoparticles. The results indicated that the uptake of cerasomes by HUVECs was a concentration-, time-, and energy-dependent process and occurred probably through a process of clathrin-mediated endocytosis, which resulted in rearrangement of the cell cytoskeleton. Cerasomes affected different aspects of cell function to a smaller extent than silica nanoparticles, including cell proliferation, cell cycle, cell apoptosis, endogenous ROS level and pro-inflammatory molecular expression. In a word, cerasomes are more biocompatible than silica nanoparticles due to the incorporation of the liposomal architecture into cerasomes. The preliminary data will assist in the further development of new cerasome-based delivery systems.